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| Journal of Vascular Access 2005; 6: 76 - 82 |
| Efficacy of low-dose alteplase for treatment of hemodialysis catheter occlusions |
J. Haymond1, K. Shalansky2, J. Jastrzebski3
1Pharmaceutical Sciences CSU, Vancouver General Hospital, Vancouver - Canada
2Pharmaceutical Sciences CSU, Vancouver General Hospital, Faculty of Pharmaceutical Sciences, University of British Columbia,Vancouver - Canada
3Department of Medicine, Vancouver General Hospital, Faculty of Medicine, University of British Columbia, Vancouver - Canada
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ABSTRACT
Background:Traditionally, alteplase 2 mg/lumen doses have been used to treat central venous catheter (CVC) occlusions. On January 20, 2004, our hemodialysis (HD) unit implemented a new protocol to utilize alteplase 1 mg/lumen doses for catheter occlusion.
Objectives:The objectives were to 1) assess the efficacy of low-dose alteplase in restoring HD catheter patency;
2) determine the duration of CVC patency as determined by need for further alteplase doses, or radiological or surgical line interventions; and 3) evaluate the financial implications of the new protocol.
Methods:The study was a prospective, open-label trial of 50 consecutive HD patients with permanent, tunnelled CVC lines. A treatment course consisted of 1 or 2 doses of alteplase instilled for 60 minutes then aspirated or as an overnight (48-72 hour) dwell until the next HD. The patient’s first alteplase dose following implementation of the new protocol was evaluated. Patients were followed for two months to record need for further al-teplase
treatment courses, and four months to document radiological or surgical line interventions. The primary outcome was to assess successful restoration of catheter patency defined as the ability of alteplase to restore or maintain HD blood flow rate at or above 300 mL/minute. A financial analysis compared alteplase costs for
11 months prior to and after implementation of the new protocol.
Results:Alteplase 1 mg/lumen doses restored catheter patency in 72% of HD patients with one dose, increasing to 83% with a second dose. Sixty-two percent of patients required a subsequent alteplase course with a median time to next treatment of 14 days and a median of 2 courses/patient. Radiological interventions were ordered in 38% of patients resulting in 8 lines replacements and 7 line strippings. Financial savings with the new low-dose
protocol were ~CDN$22,000.
Conclusion:Low dose alteplase 1 mg/lumen successfully treated occlusion of permanent hemodialysis catheters, with a resulting cost reduction.
Key Words. Alteplase, Hemodialysis, Central venous catheter
INTRODUCTION
Despite recent initiatives encouraging arteriovenous fistula (AVF) creation for long-term hemodialysis (HD) access, a substantial number of patients present with previously undiagnosed chronic renal failure (1). In these cases, provision of adequate dialysis through a central venous catheter (CVC) is essential during the AVF maturation process. Two main complications of CVCs are catheter-related infections and occlusions. Approximately 60% of occluded catheters occur due to thrombosis with the remainder due to nonthrombotic or mechanical malfunction (2). Fibrin can deposit within the lumen or as a sleeve surrounding the catheter (fibrin sheath) within 1 week to several weeks after insertion (3). Occluded thrombotic catheters can be managed pharmacologically, surgically or radiologically (4). Since surgical and radiological interventions such as thrombectomy, fib-rin-sheath stripping, and catheter replacement are expensive procedures and pose potential risk to the patient, pharmacological therapy using thrombolytic agents to preserve line patency is the preferred initial treatment for catheter occlusion (4). Thrombolytics catalyze the conversion of plasminogen to plasmin, enabling lysis of fibrin clots. Alteplase, or tissue plasminogen activator (tPA), is the preferred thrombolytic for lysing occluded catheters (4). The National Kidney Foundation – Dialysis Outcomes Quality Initiative guidelines (K/DOQI) define HD catheter malfunction as a failure to maintain an extracorporeal blood flow rate greater than or equal to 300 mL/minute (5). For the treatment of catheter-related thrombosis, instillation of alteplase 2 mg per catheter lumen has been recommended based on case reports and small studies (69). Alteplase dwell times range from 30 to 120 minutes or overnight dwells up to 72 hours. A pushpause method of alteplase administration has also been suggested (7, 10). The only randomized, placebo-controlled trial of alteplase 2 mg/lumen in 149 non-HD patients demonstrated a 74% success rate after one dose with a dwell time of 2 hours (11). The minimum effective dose of alteplase is unknown (12); however, recent literature has shown efficacy rates ranging from 70 to 85% in treating catheter occlusions with 1 mg/lumen doses of alteplase in both HD and non-HD catheters (4, 12, 13). One prospective, randomized trial compared two doses of alteplase (1 mg/lumen versus 2 mg/lumen) in 41 occluded Hickman catheters and 20 occluded implanted ports utilizing a thrombolytic dwell time of 60 minutes (13). Catheter clearance rates were similar at 81.1% for the 1 mg strength and 83.3% for the 2 mg strength. Specifically in HD patients, a retrospective analysis of 27 patients who received alteplase 1 mg/lumen using a push-pause method found a 70% success rate in ability to achieve HD blood flow rates greater than 300 mL/minute (4). The original protocol adopted in our HD unit for occluded CVCs was to instil up to 2 mg (2 mL) of alteplase to fill the internal volume of each catheter lumen plus 0.2 mL. For catheter volumes greater than 2 mL, normal saline (NS) was added to reach the required volume. Alteplase remained in situ for either 60 minutes or until the next dialysis session
(i.e. for 48-72 hours). On the basis of evidence sug-gesting comparable efficacy with low-dose alteplase and potential for significant financial benefit, on January 20, 2004, our HD unit instituted a new protocol utilizing alteplase 1 mg (1 mL) per lumen doses and adding NS to catheter volume plus 0.2 mL (Appendix 1). The only amendment to this protocol from the previous protocol was the decrease in alteplase dose. The objectives of this study were to: 1) assess the efficacy of low-dose alteplase in restoring HD catheter patency; 2) to determine the duration of catheter line patency following alteplase instillation; and 3) to evaluate the financial implications of this new protocol.
METHODS
Patients
The study was a prospective one-year analysis initiating January 20, 2004 when the new alteplase protocol of 1 mg/lumen was implemented. Approval to conduct the trial was obtained by the institution’s Research Ethics Board. All patients in a 167-bed tertiary care HD unit requiring alteplase to clear an occluded permanent, tunnelled CVC were included. The enrolment target was 50 patients and each patient was analyzed only once. Patients were excluded if they were receiving alteplase on a routine basis for prophylaxis or if they were receiving HD via a temporary, non-tunnelled catheter. Patients received one of three permanent dual lumen catheters that were inserted either radiologically (~80%) or surgically (~20%): Opti-Flow (Bard Canada Inc, Mississauga, ON), Hemoglide (Bard Canada Inc, Mississauga, ON) or CardioMed (CardioMed Supplies Inc, Gormley, ON). All patients were dialyzed for 3.5-4 hours using high-flux dialyzer membranes. For patients not receiving alteplase, heparin was used to maintain catheter patency between dialysis treatments. The heparin catheterlock dosage varied from 10,000 units/lumen prior to November 2003, 1000 units/mL from November 2003 to May 2004, and 5000 units/lumen thereafter.
Study design
Patients were identified as having catheter dysfunction by HD nursing staff on the basis of difficulty or inability to aspirate from the venous or arterial line, sluggish lines, necessity to reverse lines, and/or poor HD blood flow rates less than 300 mL/ minute. Nurses were expected to follow a standard protocol whereby 10 mL of normal saline was forcefully flushed through the occluded lumen at least twice in an attempt to restore patency (Appendix 1). If unsuccessful, alteplase 1mg/lumen was prescribed to dwell in each catheter for either 60 minutes if there was a complete occlusion, after which dialysis was initiated, or as an overnight dwell between dialysis treatments for partial occlusions. Alteplase 1 mg/mL was instilled into each catheter lumen, followed by sufficient amount of NS to fill the lumen volume of the catheter plus 0.2 mL. Alteplase was supplied in pre-filled frozen syringes of 1 mg/mL that were prepared by a central pharmacy from alteplase 50 mg vials (Activase®, Hoffmann-La Roche Ltd, Mississauga, ON) until May 2004. This product has a stability of 6 months when frozen to a temperature of 20 °C (14). In June 2004, alteplase 2 mg/2 mL vials (Cathflo®, Hoff-mann-La Roche Ltd, Mississauga, ON) were supplied to the HD unit and the pre-filled syringes were no longer used. The first alteplase dose received post-implementa-tion of the new low-dose protocol was analyzed. If patients had received an alteplase treatment within one week prior to this initial dose, the next closest dose was analyzed provided the minimum required time interval of one week had elapsed between alteplase doses. If necessary, the alteplase procedure could be repeated again if the initial dose was unsuccessful. A treatment course of alteplase thus consisted of 1 or 2 consecutive doses of alteplase. If greater than two treatment courses were required within 2 weeks of initial treatment, patients were to be referred to interventional radiology for a linogram.
Primary outcome measure
The primary outcome measure was the successful restoration of catheter patency following alteplase administration. Success was defined as the ability of alteplase to restore or maintain HD blood flow rates greater than or equal to 300mL/minute. For a successful outcome, HD was required to continue at a rate of greater than or equal to 300 mL/minute for at least three-quarters of the dialysis session. Additionally the patient was required to finish HD at or above this minimum rate. Our goal was to achieve a success rate of at least 70% with alteplase instillation based on 2 mg/lumen data (15).
Secondary outcome measures
Duration of line patency was assessed by requirement for further alteplase treatment courses or other non-pharmacological interventions. Patients were followed for a 2-month period after the initial alteplase dose to document further alteplase administration. If alteplase was ordered in multiple doses at the outset (e.g. alteplase instillation 3 consecutive runs), these orders were interpreted as one course in the follow-up for number of courses administered. A 4-month follow-up period was used to determine need for non-pharmacological interventions such as linograms, line stripping or line changes. A cost-analysis was performed to assess financial benefit comparing the cost of 11 months of usage with the low-dose alteplase protocol to the costs of using 2 mg/lumen alteplase doses over the same time frame the previous year (February to December 2004 versus February to December 2003, respectively). This time interval was chosen to prevent any overlap of dosing protocols as the unit transitioned to the new low-dose protocol on January 20, 2004 and usage could only be accessed on a monthly basis.
Statistics
Descriptive statistics using mean (± standard deviation) or median (range) were used to illustrate patient demographics, laboratory and outcome results, depending on the underlying distribution.
RESULTS
Fifty-six HD patients received alteplase between January 20th and December 23rd, 2004. Six patients were excluded for the following reasons: four patients had temporary lines, and two patients were receiving alteplase either after each HD session or weekly as prophylaxis to maintain catheter patency. Baseline patient characteristics are illustrated in Table I.
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TABLE 1
BASELINE PATIENT DEMOGRAPHICS
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The mean hemoglobin of 119 g/L was maintained primarily by administration of the erythropoietic agent darbepoetin. Sixty-two percent of patients were also maintained on at least one antiplatelet and/or anticoagulant drug. Forty percent of patients had one or more previous permanent CVCs prior to enrolment with a mean of 1 catheter per patient; one patient had 7 previous catheter insertions. The CVC insertion site was primarily the intrajugular vein with one patient dialyzing through a translumbar catheter. The majority of catheters had lumen volumes ≥ 2 mL; the smallest catheter volume was 1.3 mL. The median time to the first alteplase dose was 40 days; 2 patients required alteplase on the day of catheter insertion and the longest catheter life prior to receiving alteplase was 5.7 years in one patient. The mean HD blood flow rate prior to alteplase administration was 270 mL/minute (range 100 to 380 mL/minute), and in three patients dialysis was unable to be initiated. Overall, one dose of alteplase 1 mg/lumen was successful in 72% of patients, increasing to 83% when a second dose was administered (Tab. II).
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TABLE 2
PRIMARY AND SECONDARY OUTCOMES
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Twentyfour patients who received alteplase had initial blood flow rates ≥ 300 mL/minute but required thrombolysis due to sluggish flow, reversal of lines or inability to aspirate the lines. Twenty-one (88%) of these patients were successfully treated with one dose of alteplase given as an overnight dwell. Two patients in this group who failed alteplase and had flow rates decrease to less than 300 mL/minute on the next HD session did not receive a second dose of alteplase. However, their flow rates improved to greater than 300 mL/minute on the third HD session, following heparin-lock. The remaining 26 patients were treated with alteplase due to blood flow rates that had fallen below 300 mL/minute. This group demonstrated a 58% success rate with one alteplase dose, increasing to 73% following a second dose. The majority of these patients received alteplase as an overnight dwell until the next HD session. Only three patients received alteplase as a 60-minute dwell at the start of dialysis and all three were able to complete dialysis. The catheter lumen volume had no apparent impact on the alteplase success rate. Thirty percent of patients required no further interventions in the follow-up period. The remainder required either alteplase and/or radiological intervention (Tab. II). Sixty-two percent of patients required a subsequent alteplase treatment course with median time to the next course of 14 days and a median of 2 courses required per patient. Radiological interventions were ordered within 4 months of the initial alteplase dose in 38% of patients whereupon 8 lines were replaced and 7 required stripping. The cost for each pre-filled alteplase syringe was CDN$55 per 2 mg/2 mL syringe and CDN$28 per 1 mg/1 mL syringe. The hospital contract price for a 2 mg vial of Cathflo® was CDN$57.00. Between February to December 2003, CDN$67,991 worth of alteplase was used in the HD unit compared to CDN$46,024 for the same time period in 2004. This amounts to a cost savings of CDN$21,967 with the implementation of the new low-dose alteplase protocol.
DISCUSSION
Despite the general agreement that the number of autogenous fistulas should be maximized, CVCs will continue to remain a major form of vascular access for patients presenting acutely and for palliative patients with very short life expectancy for whom AVF is not a viable option. The provision of adequate HD in these patients is critical, necessitating sufficient blood flow rates through patent catheters. For this reason, we established a required blood flow rate of ≥ 300 mL/minute to correspond with the K/DOQI guidelines for adequate HD (5). Our prospective, observational study demonstrated that low-dose alteplase 1 mg/lumen was successful in restoring and/or maintaining patency in permanent, tunnelled catheters in 72% of HD patients with one dose and 83% with a second consecutive dose. In patients with initial blood flow rates ≥ 300 mL/minute, the success rate was 88% with one or two alteplase doses compared to 58% and 73%, respectively, in patients with initial flow rates < 300 mL/minute. Our overall success rate corresponds with the industry standard of 2 mg/lumen established by COOL trial investigators (11). The COOL trial was a multi-centre, double-blinded, placebocontrolled trial of 149 pediatric and adult non-HD patients evaluating alteplase 2 mg/lumen doses for dysfunctional indwelling chronic CVC devices. Patients were treated with a 2-hour dwell of study drug, followed by attempts to aspirate and infuse. Following one treatment, alteplase achieved success rates of 74% compared to 17% with placebo (p < 0.0001), which rose to 90% with a second dose. There are four small trials supporting the use of low-dose alteplase, of which two are specific to HD patients. Fink et al compared alteplase 1mg/lumen to 2 mg/lumen doses in an unblinded randomized trial of 45 adult patients (61 occluded lumens) with tunnelled catheters or implanted ports (13). Alteplase was administered using a 60-minute dwell; if catheter function was not restored following the initial dose, patients received a second dose. Success rates after one dose of alteplase were similar between groups (81.1% for 1 mg/mL vs 83.3% for 2 mg/2 mL, 95% CI 18.7% to 14.1%). Clearance rates after 2 alteplase doses were also similar at 85.5% and 87.5%, respectively. Davis et al evaluated 3 strengths of alteplase in 58 non-HD CVCs (6). Catheter clearance was initiated with alteplase 0.5 mg/lumen dwelled 60 minutes; the dose was sequentially escalated to 1 mg and 2 mg per lumen if the lower dose failed. Eighty-six percent of catheters were cleared with the 0.5 mg dose and a further 8.6% were cleared with escalation to the 1 mg dose. In a prospective, observational study of 52 episodes of catheter dysfunction in a HD unit, Nguyen et al assessed the efficacy of 1.5 mg/lumen doses of alteplase in restoring HD blood flow rates to at least 300 mL/minute (16). A 94% success rate was achieved with an alteplase dwell of either 30 minutes or overnight until the next HD session. The high success rate in this trial could be attributed to the fact that the same patient could be reenrolled for analysis and as well, criteria for a successful outcome were more relaxed. Finally, a retrospective review of 37 HD patients receiving either alteplase 1 mg/lumen or urokinase 5000 U/lumen for empiric treatment of catheter occlusion found a significantly higher success rate with alteplase in returning HD blood flow rates to greater than 300 mL/minute compared to urokinase using a pushpause method (70% vs 35%, p=0.0134) (4). While low-dose alteplase is successful in restoring catheter function, alteplase instillation remains only a temporary solution in maintaining catheter patency. The majority of patients in our study required further treatment either pharmacologically with alteplase (62%) at a median time of 14 days after initial therapy and/or radiologically with line manipulations (36%). Little et al performed a three-year prospective analysis of HD tunnelled catheters in 336 patients to assess catheter life (17). Catheter dysfunction was defined as inability to perform HD consistently at blood flow rates of 250 mL/minute or greater. A median duration of 135 days following catheter insertion to episode of catheter thrombosis or catheter failure was reported. After the first intervention, median catheter survival to the next intervention was 27 days, and further decreased to fewer than 20 days for each subsequent episode. The investigators suggested that once treatment is required for catheter dysfunction following an initial intervention, the catheter itself is likely structurally altered requiring replacement. Another trial of 60 HD patients with CVC dysfunction (blood flow rate < 250 mL/ minute) found patency rates following an alteplase dwell dropped from 78% at the next HD run to 48% two weeks later (15). The authors again suggested that alteplase was only a temporary measure in restoring CVC patency. In an effort to improve long-term catheter viability, our unit is currently trialing low dose alteplase infusions (1 mg/hour 2 hours) into the blocked catheter. An infusion may allow for better contact between the fibrinolytic and a potential fibrin sheath surrounding the outside of the catheter lumen. Limitations to this study include the lack of a prospective comparative group. Our cost analysis was based on retrospective data and an increase in the HD unit of 3 dialysis stations by study end as well as changes in heparin lock concentrations could have influenced these results. There was no strict criteria for patient selection, which was left to the discretion of the nephrologists primarily based on nursing observations of sluggish flow, inability to aspirate lines or necessity to reverse lines. Approximately half of the patients with dysfunctional lines received alteplase despite maintaining adequate HD blood flow rates according to the K/DOQI guidelines. Catheter dysfunction may have occurred due to other causes other than thrombosis. While overall improvement of blood flow rates in the majority of patients after thrombolysis does suggest the presence of a thrombotic lesion, failure of thrombolytic therapy could be due to a non-throm-botic complication such as a malpositioned line. Finally, our study of low dose alteplase is confined to patients with permanent, tunnelled catheters.
CONCLUSIONS
Despite the preference for early fistula creation, a significant proportion of patients will continue to require HD through a CVC, necessitating an aggressive protocol to maintain CVC patency and adequate blood flow. This study demonstrated that low dose alteplase 1 mg/lumen was an effective, albeit temporary measure in treating occluded permanent CVCs with a success rate of 72% after one dose and 83% with a second consecutive dose. A cost savings of ~$22.000 was realized over 11 months of using this protocol compared to the previous 2 mg/lumen protocol.
APPENDIX 1
Dysfunctional Hemodialysis Catheter Protocol
Forceful Flush
– Draw 10 mL Normal Saline (NS) in 2 10 mL syringes with Luer-lock.
– Forcefully flush with maximum force both catheter ports.
– If flush successful, attempt aspiration of blood
and perform 2-3 additional forceful flushes with aspirated blood.
– If initial flush unsuccessful, repeat steps 1-3; if still unsuccessful, attempt alteplase (tPA) instillation.
Alteplase (tPA) Instillation
– Instil alteplase 1 mg (1 mL) into each lumen, then instil sufficient amount of NS to fill internal volume of each catheter PLUS 0.2 mL. Example: for a catheter volume of 2.2 mL use 1mg/mL alteplase followed by 1.4 mL NS. Do not premix the alteplase and NS.
a) Wait 60 minutes, then attempt to aspirate. Forcefully flush catheters with 10mL NS prior to start of dialysis.
OR
b) Leave alteplase in situ until the next hemodialysis. Aspirate alteplase prior to next hemodialysis run. Forcefully flush catheters with 10mL NS prior to start of dialysis.
– Protocol may be repeated on two consecutive occasions within a 2 week period; otherwise physician to be contacted for line reassessment (linogram).
Address for correspondence:
Dr. Karen Shalansky
Pharmaceutical Sciences
CSU Vancouver General Hospital
855 W12th Ave Vancouver, BC V5Z 1M9 - Canada
karen.shalansky@vch.ca
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J. Haymond
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